Natural killer cells responsiveness to physical exercise: A brief review


Natural killer cells (NK) are a group of peripheral blood lymphocytes which display cytotoxic activity against a wide range of tumour cells. They are a consistent part of the inflammatory response that is activated when either internal or external injuries occur as they are able to synthesize perforins. An important role is played by NK cells in the host defence against tumours without expressing any antigen-binding recaptor in their membrane which, however, distinguish T and B lymphocytes. NK activity appears early in the immune response, thus providing immediate protection during the time required for the activation and proliferation of cytotoxic T lymphocytes and for their differentiation into functional cells. Even though much research regarding the effects of aerobic training exercise on NK cell numbers and function, there appears to be much controversy regarding its effect. NK cells are rapidly mobilized into circulation in response to acute exercise, most likely by increased shear stress and catecholamine-induced down-regulation of adhesion molecule expression. However, tissue injury and inflammation which often accompanies strenuous exercise have been associated to post-exercise NK cell suppression. Scientific evidence indicates exercise-induced changes in NK cell redistribution and function should be strongly influenced by stress hormones including catecholamines, cortisol and prolactin as well as by soluble mediators such as cytokines and prostaglandins. The role of exercise therapy in cancer patients and survivors rehabilitation is becoming increasingly important as it is thought to modulate immunity and inflammation. However, more knowledge about the effects of exercise on immune function in these patients is needed.

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Crisafulli, A. , Tocco, F. , Melis, F. , Milia, R. and Concu, A. (2013) Natural killer cells responsiveness to physical exercise: A brief review. Open Journal of Immunology, 3, 190-200. doi: 10.4236/oji.2013.34024.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] O’Shea, J. and Ortado, J.R. (1992) The biology of the natural killer cells: Insights into the molecular basis of function. In: Lewis, C.E. and McGee, J.O. Eds., The Natural Killer Cell, Oxford University Press, Oxford, 1-40.
[2] Zhou, J., Olsen, S., Moldovan, J., Fu, X., Sarkar, F.H., Moudgil, V.K. and Callewaert, D.M. (1997) Glucocorticoid regulation of natural cytoxicity: Effects of cortisol on the phenotype and function of a cloned human natural killer cell line. Cellular Immunology, 178, 108-116.
[3] Ortado, J.R., Mantovani, A., Hobbs, D., Rubinstein, M., Pestka, S. and Herberman, R.B. (1983) Effects of several species of human leukocyte interferon on cytotoxic activity of NK cells and monocytes. International Journal of Cancer, 31, 285-289.
[4] Matera, L. and Mori, M. (2000) Cooperation of pituitary hormonr prolactin with interleukin-2 and interleukin-12 on production of interferon-gamma by natural killer and T cells. Annals of the New York Academy of Sciences, 917, 505-513.
[5] Nielsen, H.B. and Pedersen, B.H. (1997) Lymphocyte proliferation in response to exercise. European Journal of Applied Physiology and Occupational Physiology, 75, 375-379.
[6] Rhind, S.G., Gannon, G.A., Suzui, M., Shephard, R.J. and Shek, P.N. (1999) Indomethacin inhibits circulating PGE2 and reverses postexercise suppression of natural killer cell activity. American Journal of Physiology, 276, R1496-R1505.
[7] Barak, Y. and Nir, E. (1987) Chediak-Higashi syndrome. American Journal of Pediatric Hematology/Oncology, 9, 42-55.
[8] Welsh, R.M. and Vargas-Cortes, R.M. (1992) Natural killer cells in viral infection. In: Lewis, C.E. and McGee, J.O. Eds., The Natural Killer Cell, Oxford University Press, Oxford,108-150.
[9] Kuby, J. (1992) Immunology. WH Freeman and Co., New York, 304-306.
[10] Poli, A., Michel, T.M., Andrès, E., Hentges, F. and Zimmer, J. (2009) CD56 bright natural killer (NK) cells: An important NK cell subset. Immunology, 4, 458-465.
[11] Jacobs, R., Hintzen, G., Kemper, A., Beul, K., Kempf, S., Behrens, G., Sykora, K.W. and Schmidt, R.E. (2001) CD56bright NK cells differ in their KIR repertoire and cytotoxic features from CD56dim NK cells. European Journal of Immunology, 31, 3121-3126.<3121::AID-IMMU3121>3.0.CO;2-4
[12] Cooper, M.A., Fehniger, T.A. and Caligiuri, M.A. (2001) The biology of human natural killer-cell subsets. Trends in Immunology, 22, 633-640.
[13] Nagler, A., Lanier, L.L., Cwirla, S. and Phillips, J.H. (1989) Comparative studies of human FcRIII-positive and negative natural killer cells. The Journal of Immunology, 143, 3183-3191.
[14] Hoffman-Goetz, L. and Pedersen, B.K. (1994) Exercise and the immune system: A model of the stress response? Immunology Today, 15, 282-287.
[15] Del Giacco, S.R., Manconi, P.E. and Del Giacco, G.S. (2001) Allergy and sports. Allergy, 56, 215-223.
[16] Nieman, D.C. (1994) Exercise, infection, and immunity. International Journal of Sports Medicine, 15, S131-S141.
[17] Walsh, N.P., Gleeson, M., Shephard, R.J. et al. (2011) Position statement, Part one: Immune function and exercise. Exercise Immunology Review, 17, 6-63.
[18] Shek, P.N. and Shephard, R.J. (1998) Physical exercise as a human model of limited inflammatory response. Canadian Journal of Physiology and Pharmacology, 76, 589-597.
[19] Nieman, D.C. and Nehlsen-Cannarella, S.L. (1992) Exercise and Infection. In: Watson, R.R., Eisinger, M. and Boca Raton, F.L., Eds., Exercise and Disease, CRC Publishers, New York, 121-148.
[20] Thune, I. and Furberg, A.S. (2001) Physical activity and cancer risk: Dose-response and cancer, all sites and site-specific. Medicine & Science in Sports & Exercise, 33, S530-S550.
[21] Mooren, F.C., Lechtermann, A. and Volker, K. (2004) Exercise-induced apoptosis of lymphocytes depends on training status. Medicine & Science in Sports & Exercise, 36, 1476-1483.
[22] Neubauer, O., Reichhold, S., Nersesyan, A., Koenig, D. and Wagner, K.H. (2008) Exercise induced DNA damage: Is there a relationship with inflammatory responses? Exercise Immunology Review, 14, 51-72.
[23] Baslund, B., Lyngberg, K., Andersen, V., Halkjaer, K.J., Hansen, M., Klokker, M. and Pedersen B.K. (1993) Effect of 8 wk of bicycle training on the immune system of patients with rheumatoid arthritis. Journal of Applied Physiology, 75, 1691-1695.
[24] Shinkai, S., Shore, S., Shek, P.N. and Shephard, R.J. (1992) Acute exercise and immune function. Relationship between lymphocyte activity and changes in subset counts. International Journal of Sports Medicine, 13, 452-461.
[25] Van Der Pompe, G., Bernards, N., Kavelaars, A. and Heijnen, C. (2001) An exploratory study into the effect of exhausting bicycle exercise on endurance and immune responses in post-menopausal women: relationships between vigour and plasma cortisol concentrations and lymphocyte proliferation following exercise. International Journal of Sports Medicine, 22, 447-453.
[26] Mackinnon, L.T., (1989) Exercise and natural killer cells. What is the relationship? Sports Medicine, 7, 141-149.
[27] Pedersen, B.K., Tvede, N., Christensen, L.D., Klarlund, K., Kragbak, S. and Halkjr-Kristensen, J. (1989) Natural killer cell activity in peripheral blood of highly trained and untrained persons. International Journal of Sports Medicine, 10, 129-131.
[28] Nieman, D.C., Miller, A.R., Henson, D.A., Warren, B.J., Gusewitch, G., Johnson, R.L., Davis, J.M., Butterworth, D.E. and Nehlsen-Cannarella, S.L. (1993) Effects of high-vs moderate-intensity exercise on natural killer cell activity. Medicine & Science in Sports & Exercise, 25, 1126-1134.
[29] Palmo, J., Asp, S., Daugaard, J.R., Richter, E.A., Klokker, M. and Pedersen, B.K. (1995) Effect of eccentric exercise on natural killer cell activity. Journal of Applied Physiology, 78, 1442-1446.
[30] Nielsen, H.B., Secher, N.H., Kappel, M., Hanel, M.B. and Pedersen, B.K. (1996) Lymphocyte, NK and LAK Cell Responses to Maximal Exercise. International Journal of Sports Medicine, 17, 60-65.
[31] Shephard, R.J. and Shek, P.N. (1999) Effects of exercise and training on natural killer cell counts and cytolytic activity. Sports Medicine, 28, 177-195.
[32] Fairey, A.S., Courneya, K.S., Field, C.J., Bell, G.J., Jones, L.W. and Mackey, J.R. (2005) Randomized controlled trial of exercise and blood immune function in postmenopausal breast cancer survivors. Journal of Applied Physiology, 98, 1534-1540.
[33] Campbell, P.T., Wener, M.H., Sorensen, B., Wood, B., Chen-Levy, Z., Potter, J.D., McTiernan, A. and Ulrich, C.M. (2008) Effect of exercise on in vitro immune function: A 12-month randomized, controlled trial among postmenopausal women. Journal of Applied Physiology, 104, 1648-1655.
[34] Gleeson, M., McDonald, W.A., Cripps, A.W., Pyne, D.B., Clancy, R.L. and Fricker, P.A. (1995) The effect on immunity of long-term intensive training in elite swimmers. Clinical & Experimental Immunology, 102, 210-216.
[35] Suzui, M., Kawai, T., Kimura, H., Takeda, K., Yagita, H., Okumura, K., Shek, P.N. and Shephard, R.J. (2004) Natural killer cell lytic activity andCD56dim andCD56bright cell distributions during and after intensive training. Journal of Applied Physiology, 96, 2167-2173.
[36] Jonsdottir, I.H., Hellstrand, K., Thoren, P. and Hoffmann, P. (2000) Enhancement of natural immunity seen after voluntary exercise in rats. Role of central opioid receptors. Life Sciences, 66, 1231-1239.
[37] MacNeil, B. and Hoffman-Goetz, L. (1993) Chronic exercise enhances in vivo and in vitro cytotoxic mechanisms of natural immunity in mice. Journal of Applied Physiology, 74, 388-395.
[38] Jadeski, L. and Hoffman-Goetz, L. (1996) Exercise and in vivo natural cytotoxicity against tumour cells of varying metastatic capacity. Clinical & Experimental Metastasis, 14, 138-144.
[39] Timmons, B.W. and Cieslak, T. (2008) Human natural killer cell subsets and acute exercise: A brief review. Exercise Immunology Review, 14, 8-23.
[40] Hoffman-Goetz, L. (1998) Influence of physical activity and exercise on innate immunity. Nutrition Reviews, 56, S126-S130.
[41] Gannon, G., Shek. P.N. and Shephard, R.J. (1995) Natural killer cells: Modulation by intensity and duration of exercise. Exercise Immunology Review, 1, 26-48.
[42] Woods. J.A., Evans, J.K., Wolters, B.W., Ceddia, M.A. and McAuley, E. (1998) Effects of maximal exercise on natural killer (NK) cell cytotoxicity and responsiveness to interferon alpha in the young and old. The Journals of Gerontology, Series A: Biological Sciences and Medical Sciences, 53, B430-B437.
[43] Gleeson, M. and Bishop, N.C. (2005) The T cell and NK cell immune response to exercise. Annals of Transplantation, 10, 43-48.
[44] Suzui, M., Takeda, K., Yagita, H., Okumura, K., Shek, P.N. and Shephard, R.J. (2005) Changes in the proportion of CD56dim and CD56bright natural killer cells during incremental exercise. Medicine & Science in Sports & Exercise, 37, S373.
[45] Suzui, M., Takeda, K., Yagita, H., Okumura, K., Shek, P.N. and Shephard, R.J. (2006) Changes in the proportions of CD56dim and CD56bright natural killer cells during and after acute exercise. Medicine & Science in Sports & Exercise, 38, S413.
[46] Nieman, D.C. (1997) Immune response to heavy exertion. Journal of Applied Physiology, 82, 1385-1394.
[47] Nielsen, H.B. and Pedersen, B.K. (1997) Lymphocyte proliferation in response to exercise. European Journal of Applied Physiology and Occupational Physiology, 75, 375-379.
[48] Gannon, G.A., Rhind, S.G., Suzui, M., Zamecnik, J., Sabi- ston, B.H., Shek, P.N. and Shephard, R.J. (1998) Beta-endorphin and natural killer cell cytolytic activity during prolonged exercise. Is there a connection? American Journal of Physiology, 275, R1725-R1734.
[49] Klokker, M., Kjaer, M., Secher, N.H., Hanel, B., Worm, L., Kappel, M. and Pedersen, B.K. (1995) Natural killer cell response to exercise in humans: Effect of hypoxia and epidural anesthesia. Journal of Applied Physiology, 78, 709-716.
[50] Kotani, T., Aratake, Y., Ishiguro, R., Yamamoto, I., Uemura, Y., Tamura, K. and Ohtaki, S. (1997) Influence of physical exercise on large granular lymphocytes, Leu-7 bearing mononuclear cells and natural killer activity in peripheral blood-NK-cell and NK-activity after physical exercise. Nihon Ketsueki Gakkai Zasshi, 50, 1210-1216.
[51] Del Giacco, S., Tocco, F., Melis, F., Crisafulli, A., Gessa, M., Santoboni, U., Del Giacco, S.G. and Concu, A. (2004) Responsiveness of human natural killer cells during acute, incremental exercise up to exhaustion. Sport Sciences for Health, 1, 36-40.
[52] Crisafulli, A., Pittau, G.L., Lorrai, L., Carcassi, A.M., Cominu, M., Tocco, F., Melis, F. and Concu, A. (2006) Poor reliability of heart rate monitoring to assess oxygen consumption during field training. International Journal of Sports Medicine, 27, 55-59.
[53] Northoff, H., Enkel, S. and Weinstock, C. (1995) Exercise, injury, and immune function. Exercise Immunology Review, 1, 1-25.
[54] Ihara, H., Shino, Y., Morita, Y., Kawaguchi, E., Ashizume, N. and Yoshida, M. (2001) Is skeletal muscle damaged by the oxidative stress following anaerobic exercise? Journal of Clinical Laboratory Analysis, 15, 239-243.
[55] Klapcinska, B., Iskra, J., Poprzecki, S. and Grzesiok, K. (2001) The effects of sprint (300 m) running on plasma lactate, uric acid, creatine kinase and lactate deydrogenase in competitive and untrained men. Journal of Sports Medicine and Physical Fitness, 41, 306-311.
[56] De Vries, W.R., Bernards, N.T., De Rooij, M.H. and Koppeschaar, H.P. (2000) Dynamic exercise discloses different time-related responses in stress hormones. Psychsomatic Medicine, 62, 866-872.
[57] Bagby, G.J., Crouch, L.D. and Shepherd, R.E. (1996) Exercise and cytochines: Spontaneous and elicited responses. In: Hoffman-Gortz, L. and Boca Raton, F.L., Eds., Exercise and Immune Function, CRC press, New York, 55-77.
[58] Gallant, S.P., Underwood, S., Durisetti, L. and Insel, P.A. (1978) Characterization and high affinity of β2-adrenergic receptor binding by (-)-[3H]-dihydroprenolol binding to human polymorphonuclear particles. Journal of Clinical Laboratory Analysis, 92, 613-618.
[59] Kappel, M., Tvede, H., Galbo, P., Haahr, P.M., Kjaer, M., Linstow, M., Klarlund, K. and Pedersen, B.K. (1991) Evidence that the effect of physical exercise on NK cell activity is mediated by epinephrine. Journal of Applied Physiology, 70, 2530-2534.
[60] Klokker, M., Secher, N.H., Madsen, P. and Pedersen, B.K. (1997) Adrenergic β1-and β1+2-receptor blockade suppress the natural killer cell response to head-up tilt in humans. Journal of Applied Physiology, 83, 1492-1498.
[61] Gabriel, H.H. and Kindermann, W. (1998) Adhesion molecules during immune response to exercise. Canadian Journal of Physiology Pharmacology, 76, 512-523.
[62] Nagao, F., Suzui, M., Takeda, K., Yagita, H. and Okumura, K. (2000) Mobilization of NK cells by exercise: Down-modulation of adhesion molecules on NK cells by cathecolamines. American Journal of Physiology. Regulatory Integrative and Comparative Physiology, 279, R1251-R1256.
[63] Nomoto, Y., Karasawa, S. and Uehara, K. (1994) Effects of hydrocortisone and adrenaline on natural killer cell activity. British Journal of Anaesthesia, 73, 318-321.
[64] Shakhar, G. and Ben-Eliyahu, S. (1998) In vivo beta-adrenergic stimulation suppresses natural killer activity and compromises resistance to tumor metastasis in rats. Journal of Immunology, 160, 3251-3258.
[65] Knudsen, J.H., Kjaersgaard, E., Jensen, E.W. and Christensen, N.J. (1994) Percentage of NK-cells in peripheral blood in resting normal subjects is negatively correlated to plasma adrenaline. Scandinavian Journal of Clinical & Laboratory Investigation, 54, 221-225.
[66] Nieman, D.C., Nehlsen-Cannarella, S.L., Donohue, K.M., Chritton, D.B., Haddock, B.L., Stout, R.W. and Lee, J.W. (1991) The effects of acute moderate exercise on leuchocyte and lymphocyte subpopulations. Medicine & Science in Sports & Exercise, 23, 578-585.
[67] Field, C.J., Gougeon, R. and Marliss, E.B. (1991) Circulating mononuclear cell numbers and function during intense exercise and recovery. Journal of Applied Physiology, 71, 1089-1097.
[68] Harizi, H. (2013) Reciprocal crosstalk between dendritic cells and natural killer cells under the effects of PGE2 in immunity and immunopathology. Cellular & Molecular Immunology, 10, 213-221.
[69] Holt, D.H., Ma, X., Kundu, N., Collin, P.D. and Fulton, A.M. (2012) Modulation of host natural killer cell functions in breast cancer via prostaglandin E2 receptors EP2 and EP4. Journal of Immunotherapy, 35, 179-188.
[70] Zeddou, M., Greimers, R., de Valensart, N., Nayjib, B., Tasken, K., Boniver, J., Moutschen, M. and Rahmouni, S. (2005) Prostaglandin E2 induces the expression of functional inhibitory CD94/NKG2A receptors in human CD8+ T lymphocytes by a cAMP-dependent protein kinase A type I pathway. Biochemical Pharmacology, 70, 714-724.
[71] Uchida, M.C., Nosaka, K., Ugrinowitsch, C., Yamashita, A., Martins, Jr. E., Moriscot, A.S. and Aoki, M.S. (2009) Effect of bench press exercise intensity on muscle soreness and inflammatory mediators. Journal of Sports Sciences, 27, 499-507.
[72] Gatti, C., Cavallo, R., Sartori, M.L., Del Ponte, D., Masera, R., Salvadori, A., Carignola, R. and Angeli, A. (1987) Inhibition by cortisol of human natural killer (NK) cell activity. Journal of Steroid Biochemistry, 26, 49-58.
[73] Singh, A., Zelazowska, E.B., Petrides, J.S., Raybourne, R.B., Sternberg, E.M., Gold, P.W. and Deuster, P.A. (1996) Lymphocyte subset responses to exercise and glucocorticoid suppression in healthy men. Medicine & Science in Sports & Exercise, 28, 822-828.
[74] Wrona, D., Trojniar, W., Borman, A., Ciepielewski, Z. and Tokarski, J. (2001) Stress-induced changes in peripheral natural killer cell cytotoxicity in pigs may not depend on plasma cortisol. Brain, Behavior, and Immunity, 15, 54-64.
[75] Luger, A., Watschinger, B., Deuster, P., Svoboda, T., Clodi, M. and Chrousos, G.P. (1992) Plasma growth hormone and prolactin responses to graded levels of acute and to a lactate infusion. Neuroendocrinology, 56, 112-117.
[76] De Meirleir, K.L., Baeyens, L., L’Hermite-Baleriaux, M. and Hollman, W. (1985) Exercise-induced prolactin release is related to anaerobiosis. Journal of Clinical Endicrinology Metabolism, 60, 1250-1252.
[77] Melis, F., Crisafulli, A., Rocchitta, A., Tocco, F. and Concu, A. (2003) Does reduction of blood prolactin levels indicate high activity of dopaminergic systems deputated to rewarding in top athletes? Medical Hypotheses, 61, 133-135.
[78] Chambers, W.H., Amscato, A.A., Smith, M.S., Kenniston, T.W., Herberman, R.B. and Appasamy, P.M. (1995) Prolactin receptor expression by rat NK cells. Natural Immunity, 14, 145-156.
[79] Vidaller, A., Guadarrama, F., Llorente, L., Mendez, J.B., Larrea, F., Villa, A.R. and Alarcon-Segovia, D. (1992) Hyperprolactinemia inhibits natural killer (NK) cell function in Vivo and its bromocriptine treatment not only corrects it but makes it more efficient. Journal of Clinical Immunology, 12, 210-215.
[80] Shinkai, S., Shore, S., Shek, P.N. and Shephard, R.J. (1992) Acute exercise and immune function—Relationship between lymphocyte activity and changes in subset counts. International Journal of Sports Medicine, 13, 452-461.
[81] Tvede, N., Kappel, M., Halkjoer-Kristensen, J., Galbo, H. and Pedersen, B.K. (1993) The effect of light, moderate and severe bicycle exercise on lymphocyte subsets, natural and lymphokine activated killer cells, lymphocyte proliferative response and interleukin 2 production. International Journal of Sports Medicine, 14, 275-282.
[82] Shek, P.N., Sabiston, B.H., Buguet, A. and Radomski, M.W. (1995) Strenuous exercise and immunological changes: A multiple-time-point analysis of leuchcyte subsets, CD4/CD8 ratio, immunoglobulin production and NK cell response. International Journal of Sports Medicine, 16, 466-474.
[83] Shephard, R.J. and Shek, P.N. (1999) Effects of exercise and training on natural killer cell counts and cytolytic activity. Sports Medicine, 28, 177-195.
[84] Roecker, K., Mayer, F., Striegel, H. and Dickhuth, H.H. (2000) Increase characteristics of the cumulated excess-CO2 and the lactate concentration during exercise. International Journal of Sports Medicine, 21, 419-423.
[85] Kruijsen-Jaarsma, M., Révész, D., Bierings, B., Buffart, L.M. and Takken, T. (2013) Effects of exercise on immune function in patients with cancer: A systematic review. Exercise Immunology Review, 19, 120-143.
[86] Inbar, S., Neeman, E., Avraham, R., Benish, M., Rosenne, E. and Ben-Eliyahu, S. (2011) Do stress responses promote leukemia progression? An animal study suggesting a role for epinephrine and prostaglandin-E2 through reduced NK activity. PLoS ONE, 6, Article ID: E19246. http://www.ncbi. MC3084788/

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